Contact Information

University Of Illinois at Chicago

Dept. Of Biochemistry and

Molecular Genetics

900 S. Ashland (M/C 669)
Chicago, IL 60607
tel: 312-996-7670
fax: 312-413-0353

Regulation of the immune response to tumors, immunomodulation by anticancer drugs and gene therapy.

Our studies are aimed at elucidating the mechanisms through which the widely used anticancer drug melphalan leads to the appearance of potent tumor-eradicating immunity in hitherto immunosuppressed mice bearing a large tumor and extensive metastases. Thus far, we have demonstrated that the immunomodulatory activity of melphalan in mice bearing the weakly immunogenic MOPC-315 tumor is manifested in the reduction of the production of cytokines with suppressive activity for the generation of cell-mediated antitumor immunity (i.e., type-2 cytokines such as TGF-b and IL-10) and the appearance of cytokines with potentiating activity for the generation of cell-mediated antitumor immunity (i.e., type-1 cytokines such as TNF, IFN-g and IL-12). Studies are currently underway to elucidate the mechanisms through which melphalan brings about the shift from a type-2 to a type-1 cytokine production in tumor bearers.

Major efforts are also directed in our laboratory towards the amplification of the tumor-eradicating immunity exhibited by mice bearing a large tumor and extensive metastases. One of our approaches was stimulated by the recent suggestion that the CTLA-4 molecule, which is induced following T-cell activation, delivers a signal to down-regulate T-cell immune functions. Accordingly, we have attempted to block the delivery of the negative signal to T-cells from tumor bearing mice through the use of anti-CTLA-4 monoclonal antibody. This manipulation endued the mice with a more powerful tumor-eradicating immunity.

Finally, studies are also underway to determine if one of the reasons why immunotherapy and cytokine gene therapy are not effective against large tumors is because the tumor cells produce factors that inhibit the migration of immune cells into the tumor nodules. Accordingly, we will attempt to improve the effectiveness of type-1 cytokine gene therapy for large tumors by reducing the level of the inhibitory factors in the tumor nodules.

Selected Publications:

La Motte RN, Sharpe AH, Bluestone JA, and Mokyr MB (1998): Importance of B7-1-expressing host antigen presenting cells for the eradication of B7-2 transfected P815 tumor cells. J Immunol. 161:6552-6558.

Mokyr MB, Kalinichenko T, Gorelik L, and Bluestone JA (1998): Realization of the therapeutic potential of CTLA-4 blockade in a low-dose chemotherapy-treated tumor-bearing mice. Cancer Res. 58:5301-5304.

La Motte RN, Sharpe AH, Bluestone JA, and Mokyr M B (1999) Host B7-1 and B7-2 costimulatory molecules contribute to the eradication of B7-1-transfected P815 tumor cells via a CD8+ T cell-dependent mechanism. J Immunol. 162:4817-4823.

Donepudi, M., Quach, D.D., Kalinichenko, T., and Mokyr, M.B. Signaling through CD40 enhances Cytotoxic T Lymphocyte generation by CD8+ T-cells from mice bearing large tumors. Cancer Immunol. Immunother. 48: 153-164, 1999.

Sojka, D.K., Donepudi, M., Bluestone, J.A., and Mokyr, M.B. Melphalan and other anticancer modalities up-regulate B7-1 gene expression in tumor cells. J. Immunol. 164: 6230-6236, 2000.

Donepudi, M., Raychaudhuri, P., Bluestone, J.A., and Mokyr, M.B. Mechanism of melphalan-induced B7-1 gene expression in P815 tumor cells. J. Immunol. 166: 6491-6499, 2001.

Jovasevic, V. M., and Mokyr, M. B. Melphalan-induced expression of IFN-beta in MOPC-315 tumor bearers and its importance for the up-regulation of TNF-alpha gene expression. J. Immunol. 167: 4895-4901, 2001.

Sojka, D. K., Felnerova, D., and Mokyr, M. B. Anti-metastatic activity of hapten-modified autologous tumor cell vaccine in an animal tumor model. Cancer Immunol. Immunother. 51: 200-208, 2002.

Jovasevic, V. M., Gorelik, L., Bluestone, J. A., and Mokyr M. B. Importance of IL-10 for the inhibitory activity of CTLA-4 ligation for tumor-eradicating immunity. J. Immunol. 172: 1449-1454, 2004.

Mokyr, M. B., Place, A. T., Artwohl, J. E., and Valli, V. E. T. Importance of signaling via the IFN-alpha/beta receptor on host cells for the realization of the therapeutic benefits of cyclophosphamide for mice bearing a large MOPC-315 tumor. Cancer Immunol. Immunother. 55: 459-468, 2006.